1,2,4 oxadiazole compounds and methods of use thereof

Abstract

The invention relates to 1,2,4 oxadiazole compounds and analogs thereof, represented by formula (II), and compositions and methods of use thereof.

What is claimed is: 
     
       1. A compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         Ar 2  is bicyclic heteroaryl selected from the group consisting of azaindolyl, benzimidazolyl, benzo[d][1,3]dioxolyl, benzofuranyl, benzoxadiazolyl, benzo[d]imidazolyl, benzo[d]imidazole-2(3H)-thione, benzoisoxazole, benzoisothiazole, benzooxazole, benzooxazolone, benzo[d][1,2,3]thiadiazolyl, 1,3-benzothiazolyl, benzothiophenyl, benzo[d][1,2,3]triazolyl, 2,2-difluorobenzo[d][1,3]dioxolyl, furopyridine, imidazopyridinyl, indolyl, indazolyl, isobenzofuran, isoindolyl, oxazolopyridine, pyrazolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, and [1,2,4]triazolopyridinyl; and 
         Ar 3  is independently pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, or triazinyl, substituted independently with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, alkyl, alkylamino, alkylcarbonyl, alkylsulfonyl, amido, amino, aminoalkyl, carboxy, dialkylamino, dialkylaminoalkyl, halo, haloalkyl, haloalkylcarbonyl, heteroaryl, heterocycle, hydroxy, hydroxyalkyl, cyano, nitro, oxo, sulfonamide and dialkylsulfonylformimidamide; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein Ar 3  is pyrimidinyl or pyridazinyl. 
     
     
       3. The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein Ar 3  is independently pyridazinyl, pyridinyl, or pyrimidinyl. 
     
     
       4. The compound of  claim 1 , selected from the group consisting of
 5-(imidazo[1,5-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(1H-indol-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(2,7-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(2-methylbenzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(benzo[d][1,2,3]thiadiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(benzo[d]thiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 3-(pyridin-3-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,4-oxadiazole; 
 5-(1H-indol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(benzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(1-methyl-1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(1H-indazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one; 
 5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazole-2(3H)-thione; 
 1,3-dimethyl-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one; 
 5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2-amine; 
 6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazole; and 
 5-(benzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
       6. The composition of  claim 5 , further comprising a nicotinic acetylcholine receptor ligand. 
     
     
       7. The composition of  claim 6 , wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α4β2 ligand demonstrating a Ki value that as measured by [3H]-cytisine binding assay (Ki Cyt) of about 0.001 nanomolar to about 100 micromolar. 
     
     
       8. The composition of  claim 6 , wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α4β2 agonist or partial agonist.